Process for producing a stent for angioplasty

ABSTRACT

A stent has surface sculpturing, preferably on its outer surface only, having, for example, microspheres, having the function of increasing the actual geometric surface area of the stent, of creating undercuts and roughness to encourage the application of coatings of active or activatable agents, as well as of improving the attachment of the stent to the blood vessel wall.

This application is a continuation of application Ser. No. 10/431,557,filed May 7, 2003 now U.S. Pat. No. 7,607,208 B2, which is acontinuation of application Ser. No. 08/997,597, filed Dec. 23, 1997,now U.S. Pat. No. 6,638,302 B1, issued Oct. 28, 2003, the contents ofeach of which are hereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention concerns a stent for angioplasty and an associatedmethod of production thereof.

BACKGROUND OF THE INVENTION

The term “stent for angioplasty” is intended to indicate generallydevices intended for endoluminal application (for example, within ablood vessel) in association with the technique of percutaneoustransluminal coronary angioplasty, or PTCA, usually effected bycatheterisation of a stenotic site.

Expanding the stent at the site causes the lumen to expand giving riseto the consequent elimination of the stenosis, and the local support ofthe lumen by the stent, which is left in place expanded, avoidsrestenosis of the treated site due to the subsequent relaxation of theblood vessel wall. The use of a substantially similar structure fordeploying vascular grafts and fixing them in place has already beenproposed in the art: naturally, this possible extension of the field ofapplication should be seen as included within the ambit of the presentinvention.

For a general review of vascular stents, reference may usefully be madeto the work “Textbook of Interventional Cardiology” edited by Eric J.Topol, W. B. Saunders Company, 1994 and, in particular, to section IV ofvolume II, entitled “Coronary Stenting”.

Many patent documents have addressed this problem, for example, U.S.Pat. No. 4,776,337, U.S. Pat. No. 4,800,882, U.S. Pat. No. 4,907,336,U.S. Pat. No. 4,886,062, U.S. Pat. No. 4,830,003, U.S. Pat. No.4,856,516, U.S. Pat. No. 4,768,507 and U.S. Pat. No. 4,503,569.

The implantation of these devices, which is a factor in the treatment ofvarious cardiac diseases, may require, or at least gain particularbenefit from the possibility of being able to administer at the stentimplantation site agents or active principles (the two terms being usedbelow in an equivalent sense) having various end purposes: they may, forexample, be antithrombogenic agents or, more generally, agents fordirectly resisting restenosis of the treated site due to the formationof deposits, tissue proliferation, etc. In relation to this, referencemay usefully be made to the following works:

“Local Drug Delivery: The Development of a Drug Delivery Stent” byRichard Stack, The Journal of Invasive Cardiology, Vol. 8, n. 8, October1996, pp 396-397;

“Local Intraluminal Infusion of Biodegradable Polymeric Nanoparticles”by Louis A. Guzman et al., Circulation, 1996; 94; pp 1441-1448;

“Local Angiopeptin Delivery Using Coated Stents Reduces NeointimalProliferation in Overstretched Porcine Coronary Arteries” by Ivan DeScreerder et al., the Journal of Invasive Cardiology, Vol. 8, n. 8,October 1996, pp 215-222.

Many applicational problems arise from this mode of operation, mostlyrelated to the specific solutions adopted. For example, the problemexists of avoiding the agent or agents intended for administration inthe zone of the stent being delivered or transported to different areaswhere they may have negative or damaging effects. Other problems mayarise, for example, in ensuring the permanence and the gradual releaseover time of active substances capable of being, as it were, washed awayby the blood passing through the stent.

These problems cannot themselves be solved or avoided by recourse toother solutions such as radioactive stents or so-called biodegradablestents, as illustrated, for example, in the work “Biodegradable Stents:The Future of Interventional Cardiology?” by M. Labinaz et al; Journalof International Cardiology, Vol. 8, n. 4, 1995, pp 395-405. Radioactivestents publicly proposed so far give rise to other problems relatedessentially to the fact that, in most cases, their use assumes thetypical features of radiotherapy and/or nuclear medicine. The maindisadvantage of biodegradable stents is that, at least in the long termwhen the stent has completely or substantially degraded, there is areduction in the mechanical support of the blood vessel wall against therisk of collapse.

As a further solution for administering various kinds of activeprinciple at the stent-implantation site a solution has recently beenproposed in which at least a portion of the surface of the body of thestent (or implantation device in general) is coated with a receptorcapable of binding with a ligand formed by combining an active principlewith a substance capable of binding to the receptor.

In order for this new solution to be fully beneficial, that is, so thatit can also be used with more conventional techniques for effectivetopical administration of the active principles, it appears important toobtain a good adhesion and/or retention on the stent of the substance orsubstances with which these active principles are associated and/or areintended to be associated.

In relation to this it is therefore necessary to take account of variousconcomitant factors which often oppose one another.

In a significant number of applications it is important that the activeprinciples are present mainly, although not exclusively, on the outersurface of the stent. Conversely, it is usually desirable that the innersurface of the stent itself is as inert as possible, that is, both fromthe chemical point of view and from the point of view of the possiblemechanical anchorage of possible deposits.

This is the reason why currently available vascular stents are subjectedto a polishing process, intended to make the surface of the stent (bothinside and outside) very smooth. In relation to this, it is alsopossible to coat the stent with a layer of biocompatible material, suchas a biocompatible carbon material (deposited, for example, usingsputtering techniques), so as to confer a high degree ofhemocompatibility on the whole stent. Adopting this technique for thedeposition of such a layer, given the very small dimensions of a stentfor angioplasty, means that it is practically impossible to limit thedeposition to just the inside surface of the stent. Consequentlytherefore, the entire surface of the stent is coated with a layer which,by its nature, makes the deposition of substances on the stent itself,in fact, impossible.

A further factor should not be forgotten: a stent for angioplasty is byits nature a heavily apertured structure, usually a mesh-like structurein which, especially in the radially-extended position, the effectivesurface intended to come into contact with the blood vessel wall is asmall fraction of the theoretical tubular surface area defined by theoutside of the stent itself. In other words: even by putting the otherproblems described above to one side, there is very little availablesurface on the stent for carrying the active principles intended forlocal delivery.

The object of the present invention is that of resolving thedisadvantages described above.

In particular, the solution according to the invention, having thecharacteristics referred to in the following claims, enables theselective application, specifically to the outer surface only of thestent, of a completely effective quantity of active principle (eitherdirectly or in the form of a receptor capable of binding with a ligandcarrying the active principle) without by this losing the possibility ofhaving a very smooth surface, at least inside the stent, even if cladwith coatings such as hemocompatible carbon coatings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 6 are partial enlarged views of a segment of a stent intransverse section secondary to various embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention, which concerns a stent as well as the associatedprocedure for the manufacture thereof, will now be described withreference to the accompanying drawings, comprising FIGS. 1 to 6, whichillustrate different possible embodiments of the invention.

In all of the accompanying Figures, the reference numeral 1 indicates awall portion of a stent for angioplasty. By way of example, FIGS. 1 to 6can be considered as partial views on an enlarged scale of a segment ofa stent in transverse section. Such a section is usually circular inshape regardless of whether the stent is radially-contracted orradially-expanded.

The specific details of construction of the stent and, in particular,its geometry, are factors which are in themselves clear in the contextof the invention and which apply regardless of the particular structureof the stent. This is also substantially true as regards the basicmanufacturing technique (for example, starting from a wire or microtubewhich is then subjected to an operation for cutting the apertures, forexample, using lasers) and/or the material (usually metal) of which thestent is made. All of these factors are dealt with in a fairly largevolume of literature and do not require detailed description here.

In essence, the invention provides for the formation of surfacesculpturing on the stent 1, at least—and preferably—over a part of, orthe whole of the outer surface, indicated 2, and having substantiallythe aim of:

-   -   increasing the theoretical surface area of the stent in order to        encourage the application of coatings, such as those intended to        carry or bind active principles,    -   creating in any case undercuts and roughness so as to form        anchorage sites for the substances, without requiring specific        surface-adhesion sites, and, as a complementary advantage,    -   improving the attachment of the stent to the blood vessel wall        that is already in the acute phase, specifically by preventing        relative movements which can give rise to microlesions.

For clarity, the term “sculpturing” is used to distinguish clearly thesurface conformation attributed to the stent according to the inventionfrom the degree of surface (residual) roughness that the surfaces of thestent have in any case, even when they have been previously subjected,according to convention, to a polishing or finishing process.

By way of example, one such treatment confers such a degree of residualroughness on the stent surfaces that the peak-to-trough distancesrecognisable in a theoretical section of the surface in question atright angles to the surface itself are not, in any case, greater thanapproximately 2-3 microns.

The degree of surface irregularity, or sculpturing, characteristic ofthe invention is, instead, such that the peak-to-trough distances foundin similar conditions are, typically approximately 10-20 microns, thatis, with the possibility of achieving values of an order of magnitudeeven greater than those of the normal surface finishing of a stent.

FIGS. 1 to 6 illustrate, in order of current preference, differenttechniques that can be used to confer the desired degree of sculpturingon the surface 2.

In particular, FIG. 1 concerns the application of microspheres 3 formedfrom the same material (usually metal) as the stent or from differentmaterials with the subsequent anchorage of the microspheres (the averagediameter of which is approximately 10-20 microns) using the method knownas “hot partial melting”. This is a method known in the art and is used,for example, to confer a surface appearance approximately similar to thesurface appearance characteristic of a work-piece obtained by sinteringthe surfaces of mechanical work-pieces intended for various purposes.From this one understands that such an embodiment can be practised alsoin connection with a stent realized, as a whole, or at least in thosepart(s) corresponding to the surface sculpturing, by sintering.

FIG. 2 concerns an embodiment of the arrangement illustrated in FIG. 1in which, while retaining the same typical surface irregularity,irregular-shape granules 4 are used in place of the microspheres 3. Thesame remarks made in the foregoing in respect of possibly manufacturingthe stent, at least partly, by sintering apply also in this case.

FIG. 3 illustrates a further embodiment based on the deposition of areceptor material using, for example, sputtering or plasma spraytechniques to form an irregular-shape accretion, for example, having apseudocolumnar structure.

From this point of view, the solution according to FIG. 1 (theapplication of microspheres) seems to be preferred when it is desired tocreate undercuts and roughness on the surface 2, having a mechanicalanchorage function and precisely defined geometric characteristics whichare identified by the (precisely determinable) grain size of themicrospheres 3.

Conversely, the arrangement shown in FIG. 3 appears preferable where theobjective is to maximise the effect of increasing the theoreticalsurface area that is effectively exposed. This latter solution istherefore preferred when, for example, it is desired to apply a coatingto the surface of the stent 1, which coating transports and/or isintended to transport active principles and is essentially in the formof a monomolecular layer.

The arrangement according to FIG. 2 constitutes, to a certain extent, akind of intermediate between the arrangements of FIGS. 1 and 3.

The arrangements to which FIGS. 1 to 3 refer, which comprise possibleequivalent arrangements, are characterised essentially by the fact thatthe surface sculpturing is formed by the application to the surface 2 ofmaterial identical with or different from that of the stent 1. Thesearrangements are generally preferred when greater or smaller undercutzones are desired on the surface 2.

In any case, objects substantially similar to those described at thebeginning of this detailed description of the invention can be achievedby treating the surface 2 in ways intended to confer a generallysculpted appearance thereon.

In relation to this, FIG. 4 illustrates the results obtained bysubjecting the outer surface 2 to sand-blasting or shot-blasting (a termreserved for a treatment which—instead of using sand as insand-blasting—is effected using microspheres (“balls”) as the ballisticagents, for impact with the treated surface).

FIG. 5 illustrates the results of a mechanical scoring operation(incision or knurling) performed on the outer surface 2 of the stent.

Finally, FIG. 6 illustrates the results obtained from a localisedchemical attack (etching) of the surface 2. This method is effectedusing a resist material (for example, photoresist) which, followingexposure through masks or polymerisation using laser beams, isselectively removed from some zones of the surface 2 so as to enable theattack thereof. The resist tracks remaining on the surface 2 are thenremoved by washing.

This technology is well known in the art (for example, for themanufacture of integrated circuits) and does not need to be illustratedin great detail in this context.

Results substantially similar to those illustrated in FIG. 5 and, inparticular, FIG. 6, can also be obtained by incision using laser beams,for example, before or after the operation for cutting the stentstructure from a blank constituted by a microtube of metal.

As a rule, all of the solutions illustrated in FIGS. 1 to 6, and anyequivalents thereto, can apply to stents obtained from a metalmicrotube, possibly manufactured totally or partly by sintering, as wellas stents obtained from a wire, the processes illustrated beingperformed either before or after cutting the tube and/or winding thewire. For reasons of manufacturing simplicity, the applicant has in anycase established that it is preferred to form the surface sculpturingbefore cutting the tube or winding the wire.

1. An improved process for producing a stent for angioplasty, saidimprovement comprising: prior to cutting a microtube, creating on saidmicrotube a plurality of regions thereon for an active agent to beoptionally placed; and polishing said stent.
 2. The improved process ofclaim 1 in which said cutting further comprises cutting stent structureapertures.
 3. The improved process of claim 1 in which said regions aredesigned to locally deliver said active agent.
 4. The process of claim 1in which said cutting comprises laser cutting.
 5. The process of claim 4in which said creating comprises use of a laser.
 6. A processcomprising, applying to a microtube blank the following sequence ofsteps: first, creating a plurality of surface areas on said blank thatoptionally contact an active agent, and second, cutting a stentstructure into said microtube blank.
 7. The process of claim 6 in whichsaid cutting said microtube blank comprises cutting said blank intoindividual sections.
 8. The process of claim 6 further comprising, aftersaid first step, contacting said plurality of surface areas with saidactive agent.
 9. The process of claim 6 further comprising, after saidfirst step, contacting said plurality of surface areas with more thanone active agent.
 10. The process of claim 6 in which said active agentis selected from the group consisting of an antithrombogenic agent, anagent for resisting restenosis, and an agent to resist tissueproliferation.
 11. The process of claim 6 further comprising making aninner tubular surface of said blank.
 12. The process of claim 6 furthercomprising polishing a surface of the microtube blank.
 13. The processof claim 6 in which said microtube blank is a metal microtube blank. 14.The process of claim 6 in which said cutting comprises laser cutting.15. The process of claim 14 in which said creating comprises use of alaser.
 16. A process of forming a drug carrying stent from a microtube,the microtube having an exterior surface and an interior surfacedefining a wall thickness therebetween, the stent having a generallycylindrical structure with a plurality of apertures and a plurality oflocations for containing a drug, the apertures having a shape whichincreases in size when the stent is expanded, the locations forcontaining a drug having a shape which is substantially unchanged whenthe stent is expanded, the process comprising: controlling a lasercutting machine to cut both the apertures and the locations forcontaining a drug into the microtube during a stent forming process, thelocations for containing a drug being cut to a depth which is less thanthe wall thickness.
 17. The process of claim 16 wherein the locationsfor containing a drug are cut before the apertures are cut.
 18. Animproved process for producing a stent for angioplasty, said improvementcomprising, prior to cutting stent structure apertures into a microtube,creating on said microtube a plurality of regions thereon for an activeagent to be optionally placed.
 19. The improved process of claim 18 inwhich said regions are designed to locally deliver said active agent.20. The process of claim 18 in which said cutting comprises lasercutting.
 21. The process of claim 20 in which said creating comprisesuse of a laser.
 22. A process comprising, applying to a microtube blankthe following sequence of steps: first, creating a plurality of surfaceareas on said blank, second, cutting said microtube blank, and aftersaid first step, contacting said plurality of surface areas with saidactive agent.
 23. The process of claim 22 in which said cutting saidmicrotube blank comprises cutting said blank into individual sections.24. The process of claim 22 further comprising, after said first step,contacting said plurality of surface areas with more than one activeagent.
 25. The process of claim 22 in which said active agent isselected from the group consisting of an antithrombogenic agent, anagent for resisting restenosis, and an agent to resist tissueproliferation.
 26. The process of claim 22 further comprises making aninner tubular surface of said blank.
 27. The process of claim 22 furthercomprising polishing a surface of the microtube blank.
 28. The processof claim 22 in which said microtube blank is a metal microtube blank.29. The process of claim 22 in which said cutting comprises lasercutting.
 30. The process of claim 29 in which said creating comprisesuse of a laser.
 31. A process of forming a drug carrying stent from amicrotube, the stent having a generally cylindrical structure with aplurality of apertures and a plurality of locations for containing adrug, the apertures having a shape which increases in size when thestent is expanded, the locations for containing a drug having a shapewhich is substantially unchanged when the stent is expanded, the processcomprising: controlling a laser cutting machine to cut both theapertures and the locations for containing a drug into the microtubeduring a stent forming process, wherein the locations for containing adrug are cut before the apertures are cut.
 32. A process comprising,applying to a microtube blank the following sequence of steps: first,creating a plurality of surface areas on said blank, second, cuttingsaid microtube blank and, after said first step, contacting saidplurality of surface areas with more than one active agent.
 33. Theprocess of claim 32 in which said cutting said microtube blank comprisescutting said blank into individual sections.
 34. The process of claim 32in which said active agent is selected from the group consisting of anantithrombogenic agent, an agent for resisting restenosis, and an agentto resist tissue proliferation.
 35. The process of claim 32 furthercomprising making an inner tubular surface of said blank.
 36. Theprocess of claim 32 further comprising polishing a surface of themicrotube blank.
 37. The process of claim 32 in which said microtubeblank is a metal microtube blank.
 38. The process of claim 32 in whichsaid cutting comprises laser cutting.
 39. The process of claim 38 inwhich said creating comprises use of a laser.
 40. A process comprising,applying to a microtube blank the following sequence of steps: first,creating a plurality of surface areas on said blank that contact anactive agent, the active agent being selected from the group consistingof an antithrombogenic agent, an agent for resisting restenosis, and anagent to resist tissue proliferation, and second, cutting said microtubeblank.
 41. The process of claim 40 in which said cutting said microtubeblank comprises cutting said blank into individual sections.
 42. Theprocess of claim 40 further comprises making an inner tubular surface ofsaid blank.
 43. The process of claim 40 further comprising polishing asurface of the microtube blank.
 44. The process of claim 40 in whichsaid microtube blank is a metal microtube blank.
 45. The process ofclaim 40 in which said cutting comprises laser cutting.
 46. The processof claim 45 in which said creating comprises use of a laser.
 47. Aprocess comprising, applying to a microtube blank the following sequenceof steps: first, creating a plurality of surface areas on said blankthat optionally contact an active agent; second, cutting said microtubeblank; and wherein the process further comprises polishing a surface ofthe microtube blank.
 48. The process of claim 47 in which said cuttingsaid microtube blank comprises cutting said blank into individualsections.
 49. The process of claim 47 further comprises making an innertubular surface of said blank.
 50. The process of claim 47 in which saidmicrotube blank is a metal microtube blank.
 51. The process of claim 47in which said cutting comprises laser cutting.
 52. The process of claim51 in which said creating comprises use of a laser.
 53. A processcomprising, applying to a metal microtube blank the following sequenceof steps: first, creating a plurality of surface areas on said blankthat optionally contact an active agent, and second, cutting saidmicrotube blank.
 54. The process of claim 53 in which said cutting saidmicrotube blank comprises cutting said blank into individual sections.55. The process of claim 53 further comprising making an inner tubularsurface of said blank.
 56. The process of claim 53 in which said cuttingcomprises laser cutting.
 57. The process of claim 56 in which saidcreating comprises use of a laser.